Thursday, February 21, 2013

Beyond an Individual Burden: Epigenetics, Heritability,and Depression

By Neha Patel

Earlier this month, my friend Kristin wrote a great blog
about epigenetic changes that occur during stressful times in childhood and
adolescence, and how they contribute to adult-onset psychiatric disorders. In
this blog, I’m going to focus on the fact that these epigenetic modifications
are heritable, and may have larger implications for communities and their
future generations.

In a paper published in 2010 by Franklin et al., during
postnatal days 1-14, one group of mice were exposed to unpredictable maternal
separation and unpredictable maternal stress (MSUS). The other group was the
control, with their mother present and an unstressed environment. This F1
generation was later put through behavioral testing as adults. The F1 adults
that were exposed to MSUS showed signs of depression, indicated by more time
spent floating during a forced swim test, and also a lack of behavioral
control, which was shown by a shorter latency to enter the center of an open
field.

However, none of this is new to us. Of course a mouse that
experienced early stress would most likely be depressed and have abnormal
behavior in adulthood! The troubling part is the next step in the authors’
experiment, when they mated both F1 males (the MSUS and control) to unstressed females.
The pups of the F2 generation were all reared like the F1 control, with no
early stress, and once again behaviorally tested as adults. The results determined
that some of them had signs of depressive behavior, particularly the females, despite being raised with
love. The authors suggest that this is in line with
the complicated sex-dependent mechanism seen in humans. Luckily, treatment with an antidepressant was
able to reverse these behaviors in mice.

Fig. 1A in Franklin et al. paper. This shows the experimental design for the breeding of mice. Blue mice are control, and orange are MSUS. Black mice are the unstressed females subsequent generations are mated with.

To produce a subsequent generation of offspring (F3), the authors’ mated control and MSUS F2 males and unstressed females, and found that the
females were still displaying depressive behavior. The lab turned to molecular
techniques to determine whether there were epigenetic changes that may have
persisted through the male germline cells all the way from the F1 generation.
The candidate genes that were chosen are involved in epigenetic changes in gene
expression, and linked with depression. Methyl CpG-binding protein 2 (MeCP2), a
gene which is associated with an increased stress response when its’ expression
is deficient, was analyzed by bisulfite pyrosequencing to be hypermethylated in
both the F1 MSUS sperm, and the F2 female brains. The hypermethylation is
indicative of downregulation of expression, which was confirmed with quantitative
RT-PCR, a technique which can quantify levels of mRNA. Other candidates, such
as the cannabinoid receptor-1 (CB1), and corticotrophin-releasing factor receptor
2 (CRFR2), were also shown to be differentially methylated and downregulated in
gene expression in F1 MSUS sperm and F2 progeny female brains. The
downregulation of all these genes can contribute to the depressive-like
behavior in mice.

In conclusion, this paper shows that early postnatal stress
can alter methylation patterns in key behavioral genes in the germline of
males. Since these changes are in the germline, these patterns can persist
through generations and impact the behavior of offspring. This study was done in mice, but what would
the impact be for humans if the same mechanism was conserved?

Many communities have been impacted throughout history by
stress and separation. To name a few examples, the Holocaust, Japanese
Internment, and the refugee experiences of Vietnamese people all were stressful
events for these respective communities, and often resulted in separation of
family. Also, children who grow up in poverty experience more stress, and are
likely separated from their caretakers more often if these caretakers are
taking on multiple jobs to make ends meet. Foster children are another
population that are of concern when we are talking about a possible impact of
this research—the instability they experience from an early age can upset their
lives. This research also suggests that even if stability is reached later in
life, the epigenetic modifications can still remain and effect future
generations.

So what can we do as a society to help alleviate these
negative consequences in certain communities? For one, we have to be as
supportive and nonjudgmental of others as we can. We don’t know their life history
or even their family’s life circumstances before we come into contact with
them. As Heather suggested in her insightful blog post, we should try and err
on the side of compassion. Also, we should speak up if we see an injustice
against a community because turning a blind eye may very well result in future
harm for many generations to come.

1 comment:

This insightful blog post reminds me of this video documentary titled "Unnatural Cuases: Is Inequality Making Us Sick?" http://www.unnaturalcauses.org/ I think its important to remember how these epigenetic factors are compounded with the health and pollution disparities that still exist today.